RESUMO
Patients with Fanconi anemia subgroup D1, attributable to biallelic mutations in BRCA2, have an increased risk of solid tumors. Tumors in the kidneys of these patients are almost exclusively Wilms tumor. We report the first recorded case, to our knowledge, of a Clear Cell Sarcoma of the Kidney in a patient with this cancer predisposition syndrome. We review different aspects of the need for careful clinical observation in patients of this complementation group, given their risk for malignancy.
Assuntos
Anemia de Fanconi/complicações , Neoplasias Renais/etiologia , Sarcoma de Células Claras/etiologia , Adulto , Biópsia , Quimioterapia Adjuvante , Evolução Fatal , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Imageamento por Ressonância Magnética , Masculino , Recidiva Local de Neoplasia , Nefrectomia , Fatores de Risco , Sarcoma de Células Claras/patologia , Sarcoma de Células Claras/terapia , Falha de TratamentoRESUMO
Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest-derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.
Assuntos
Fator 1 Ativador da Transcrição/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Células Claras/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Linhagem da Célula/genética , Proliferação de Células , Expressão Gênica , Fusão Gênica , Genes fos , Humanos , Camundongos , Camundongos Transgênicos , Crista Neural/patologia , Proteínas de Fusão Oncogênica/genética , RNA Interferente Pequeno/genética , Sarcoma de Células Claras/etiologia , Sarcoma de Células Claras/patologia , Fatores de Transcrição/genéticaRESUMO
Childhood cancer survivors are at risk for developing second malignant neoplasms. Very-low-dose therapeutic radiation therapy (RT) may be used to treat infants with Stage 4S neuroblastoma. We report a case of a patient who subsequently developed clear cell sarcoma of the gastrointestinal tract nearly 15 years after treatment with very low-dose therapeutic RT (4.5 Gy) for Stage 4S neuroblastoma.
Assuntos
Neoplasias do Íleo/etiologia , Neoplasias Induzidas por Radiação/etiologia , Sarcoma de Células Claras/etiologia , Adolescente , Humanos , Neoplasias Hepáticas/radioterapia , Masculino , Neuroblastoma/radioterapia , Dosagem RadioterapêuticaAssuntos
Neoplasias do Íleo , Neoplasias Hepáticas , Segunda Neoplasia Primária , Neuroblastoma , Sarcoma de Células Claras , Adolescente , Terapia Combinada , Humanos , Neoplasias do Íleo/etiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Masculino , Neoplasias Induzidas por Radiação , Segunda Neoplasia Primária/etiologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/radioterapia , Sarcoma de Células Claras/etiologiaRESUMO
Specific chromosomal translocations are commonly present in mesenchymal tumors and frequently involve genes encoding transcription factors. The combination of different domains from unrelated genes results in chimeric proteins believed to play a key role in the neoplastic process. The EWS/ATF1 and EWS/FLI1 fusion proteins associated with Clear Cell Sarcoma and Ewing's Sarcoma, respectively, were utilized to study the comparative effect of the EWS component on two different DNA binding partners. A potential regulatory site within the EWS IQ domain at serine266 was identified, and studies were performed to demonstrate that EWS is phosphorylated in cells and phosphorylation of serine266 regulates transcriptional activity. Mutational analysis showed that elimination of phosphorylation significantly reduced DNA binding activity by EMSA and reporter activation in luciferase assays, whereas phosphorylation mimicry resulted in a partial restoration to wild-type levels. Phosphorylation was also observed to mediate cellular compartmentalization. These studies confirm that IQ domain phosphorylation regulates the transcriptional activity of exogenous EWS/ATF1 and EWS/FLI1 and suggests that post-translational modifications may potentiate the neoplastic behavior of fusion proteins in general. Since the IQ domain is incorporated into only a subset of fusion transcripts, these findings may provide insight into the molecular mechanism underlying clinical heterogeneity observed in Ewing's sarcoma.
Assuntos
Proteínas de Fusão Oncogênica/metabolismo , Ribonucleoproteínas/metabolismo , Sarcoma de Células Claras/etiologia , Sarcoma de Ewing/etiologia , Fatores de Transcrição/metabolismo , Células 3T3 , Animais , DNA/metabolismo , Éxons , Ribonucleoproteínas Nucleares Heterogêneas , Camundongos , Proteínas de Fusão Oncogênica/genética , Fosforilação , Proteína Proto-Oncogênica c-fli-1 , Proteína EWS de Ligação a RNA , Ribonucleoproteínas/química , Ribonucleoproteínas/genética , Serina/metabolismo , Fatores de Transcrição/genéticaRESUMO
Los leiomiosarcomas localizados en las partes blandas superficiales son neoplasias muy raras o infrecuentes, tanto en las formas primarias como en el caso de las formas secundarias o metastásicas. Presentamos el caso de un leiomiosarcoma cutáneo primario en una mujer de 42 años de edad y realizamos una revisión de sus características clínicas y diagnóstico, así como de las diferencias pronóstico-evolutivas según las distintas localizaciones de esta afección. Por último, debe señalarse que el tratamiento es fundamentalmente quirúrgico, con escisión con márgenes de seguridad, ya que no existe una respuesta satisfactoria o significativa al tratamiento radio y/o quimioterápico, siendo imprescindible y obligado efectuar un seguimiento periódico de los enfermos debido a la tasa de recurrencia local y la posibilidad de metastatizar según la localización histológica del tumor (AU)
